Gene Mutation Might Explain Why Some People Don’t Get Sick From Covid-19: Study

People who get COVID-19 but never develop symptoms, known as super dozers, may have a heritable advantage. They are more than twice as likely as others to have a specific gene variation that aids in virus elimination, according to a new study led by researchers at UC San Francisco.

The paper, published in Nature on July 19, 2023, presents the first evidence that there is a genetic basis for asymptomatic SARS-CoV-2. The research helps to solve the mystery of why some people can be infected with COVID-19 without becoming ill.

The secret lies in human leukocyte antigens (HLA), or protein markers that signal to the immune system. A mutation in one of the genes coding for HLA appears to help virus-killing T cells to recognize SARS-CoV-2 and launch a light attack.

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The T cells of some people with this variant can recognize the new coronavirus even if they have never encountered it before, due to its similarity to seasonal cold viruses they already know. The discovery points to new targets for drugs and vaccines.

“If you have an army that is able to identify the enemy early, that’s a huge advantage,” explained the study’s lead researcher, Jill Hollenbach, PhD, MPH, professor of neurology, as well as epidemiology and biostatistics, and a member of the Weill Institute for Neurosciences at UCSF. “It’s like soldiers who are prepared for battle and already know what to look for, and these are the bad guys.”

The mutation – HLA-B15:01 – is quite common, occurring in about 10% of the population studied. It does not stop the virus from infecting cells, but prevents people from developing any symptoms. This includes a runny nose or even a barely noticeable sore throat.

UCSF researchers found that 20% of study participants who remained symptom-free after infection had at least one copy of the HLA-B* 15:01 variant, compared to 9% of those who reported symptoms. Those who carried two copies of the variant were far more likely – more than eight times – to avoid feeling ill.

Taking advantage of the National Marrow Donor Database

The researchers already suspected that HLA was involved, and fortunately there existed a national registry that had the data they were looking for. The National Marrow Donor Program/Be the Match, the largest registry of HLA-typed volunteer donors in the US, matches donors with people who need bone marrow transplants.

But they still need to know how the donors fared against COVID-19. So, they turned to a mobile app developed at UCSF called the COVID-19 Citizen Science Study. They recruited nearly 30,000 people who were also in the bone marrow registry and were followed during the first year of the pandemic. At the time, vaccines were not yet available, and many people were undergoing routine COVID testing for work or whenever they potentially came into contact.

“We didn’t plan to conduct the genetics study, but we were thrilled to see this result from our multidisciplinary collaboration with Dr. Hollenbach and the National Marrow Donor Program,” said Mark Pletcher, MD, MPH, professor of epidemiology and biostatistics at UCSF.

The primary study group was limited to those who self-identified as white because there were not enough people from other ethnic and racial groups to analyze the final group of study respondents.

The researchers identified 1,428 unvaccinated donors who tested positive between late February 2020 and April 2021, before vaccines were widely available and when test results still took several days to come back.

Of these, 136 persons were asymptomatic for at least two weeks before and after testing positive. Only one of the HLA variants – HLA-B15:01 – had a strong association with asymptomatic COVID-19 infection, and this was reproduced in two independent cohorts. Risk factors for severe COVID-19, such as older age, being overweight and having chronic diseases like diabetes, do not appear to play a role in remaining asymptomatic.

Martin Myers, Vice President of Research at the National Marrow Donor Program/Be the Match, said, “We are proud to partner with the National Registry to help find cures for diseases and improve our ability to prevent future pandemics. has the potential to leverage long-term public investment in the construction of

To find out how HLA-B15 managed to evade the virus, Hollenbach’s team collaborated with researchers from La Trobe University in Australia. He considered the concept of T-cell memory, through which the immune system remembers past infections.

The researchers looked at T cells from people who had HLA-B15 but had never been exposed to the SARS-CoV-2 virus, and found that these cells still reacted to a part of the novel coronavirus called the NQK-Q8 peptide. They concluded that exposure to certain seasonal coronaviruses, which contain a very similar peptide, called NQK-A8, enables T cells in these individuals to more quickly recognize SARS-CoV-2 and mount a faster, more effective immune response.

“By studying their immune response, it may enable us to identify new ways of boosting immune protection against SARS-CoV-2 that could be used in future vaccines or drug development,” said Stephanie Gras, Professor and Head of Laboratory at La Trobe University.